The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D), has attracted broad interest because of its anticancer properties. However, 1,25D and several analogues have failed as therapies because of poor efficacy or acquired resistance. Preclinical studies in cancer revealed combinatorial effects of combining 1,25D analogues with histone deacetylase inhibitors (HDACi). Hormonal 1,25D activates the vitamin D receptor (VDR), which functions as a ligand-regulated transcription factor.
The capacity of 1,25D, and its analogues, to inhibit proliferation of head and neck squamous carcinoma cells (HNSCC) has been studied (see Lin, R. et al. Molecular Endocrinology (2002) 16:1243-1256; Akutsu, N. et al. Molecular Endocrinology (2001) 15:1127-1139; Prudencio, J. et al Journal of the National Cancer Institute (2001) 93:745-753). Whereas proliferation of well-differentiated human SCC25 cells is arrested in G0/G1, poorly differentiated SCC4 cells are 1,25D-resistant. However, this resistance can be overcome by coadministration of the histone deacetylase inhibitor (HDACi) trichostatin A (TSA). Indeed, SCC4 cells are particularly sensitive to the combination of 1,25D and TSA, consistent with combinatory effects on prostate and breast cancer cell proliferation and survival (see Khanim, F. L. et al Oncogene (2004) 23:6712-6725 and Banwell, C. M. et al J Steroid Biochem Mol Biol (2004) 89-90:245-249. Nuclear HDACs can modulate gene transcription by controlling DNA-histone interactions in the nucleosome and through regulation of components of the transcription machinery. HDACi's, such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), have been investigated as anti-cancer agents and, similar to VDR agonists, HDACi's induce cell cycle arrest, cellular differentiation and/or apoptosis.
Triciferol, has a merged the secosteroidal backbone with a side chain derived from TSA and has shown both a VDR agonist and an HDACi in cells in culture, and was more efficacious in vitro than 1,25D in inhibition of SCC4 cell proliferation (see Tavera-Mendoza, L. E., et al. Proceedings of the National Academy of Sciences of the United States of America (2008) 105:8250-8255).